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REVIEW

doi:10.1038/nature11551

Reciprocal interactions of the intestinal
microbiota and immune system
Craig L. Maynard1, Charles O. Elson2, Robin D. Hatton1 & Casey T. Weaver1

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic
relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of
microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immunemediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune
system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system
integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise
for new approaches to modulate immune networks to treat and prevent disease.

E

very one of us enters the world devoid of microbial colonization
because of the sterile environment of the womb. This germfree existence is short-lived: birth exposes the newborn to
the microbiota of the mother, setting in motion the colonization of
mucosal tissues in the digestive, respiratory and urogenital tracts, and
the skin by a diverse microbiota, which we coexist with throughout
our lives. The complex and dynamic interaction between the microbiota and its human host is the culmination of nearly half a billion
years of co-evolution with vertebrates that has reciprocally shaped
the repertoires of the microbiota and the immune system, such that
the microbiota in humans is normally restrained and well-tolerated.
The scope of this interaction is particularly evident in the intestinal
tract, in which the greatest diversity and abundance of microbes reside.
Estimated at approximately 100 trillion organisms, most of which are
bacteria (although archaea and eukaryotes are also represented), the
microbiota numbers about ten times the total cells in the human body,
with the greatest density populating the distal ileum and colon1. The
collective genome, or metagenome, of the intestinal microbiota has
more than 100 times the number of genes of the human genome. Each
individual is populated by roughly 15% of the 1,000 or more species of
intestinal bacteria that have been described2, which reflects the substantial variability in the composition of the microbiota between individuals.
There are, therefore, about tenfold more genes in each of our microbiomes than in each of us, encoding the greatest source of potential
antigens for the immune system to cope with, substantially exceeding
those of self and pathogen-derived antigens.
The relationship that has been forged between the intestinal microbiota
and its human host provides mutual benefits. At homeostasis, the microbiota benefits from the warm, nutrient-rich environment of the gut so it
can establish a relatively stable ecosystem. Humans in turn benefit from
a highly adaptive metabolic engine that in addition to providing essential
non-nutrient factors, such as vitamins, also substantially increases our
ability to harvest nutrients from food. This increased digestive capacity is
mainly a result of the microbiota’s complementation of the limited diversity of complex-carbohydrate-metabolizing enzymes that are encoded
in the human genome. In addition, by establishing robust, interlinked
metabolic or nutrient networks, and biofilms among its constituents, the
microbiota limits the resources available to potential pathogens that must
outcompete well-adapted and entrenched resident microbes for metabolic

and physical niche space. Resident microbes thereby establish a microbial
buffer that limits access by those not part of the consortium.
However, the microbiota is not innocuous, and under conditions
that compromise the ability of the host to limit the microbiota’s entry
from the intestinal lumen, some species can invade host tissues to cause
disease. Furthermore, shifts in the composition of the microbiota,
whether induced by dietary changes, antibiotic treatment or invasive
pathogens, can disturb the balance of organisms in the microbiota and
alter the metabolic network of the collective to favour the outgrowth
of potentially pathogenic constituents. Referred to as dysbiosis, such
changes in the microbiota can perturb immune regulatory networks
that normally restrain intestinal inflammation, and may contribute to
immune-mediated disease directed against antigens of the microbiota.
Dysbiosis is most often associated with inflammatory bowel disease
(IBD), including Crohn’s disease and ulcerative colitis, and necrotizing enterocolitis in premature infants. But it is also increasingly linked
to a number of extraintestinal immune-mediated diseases, including
rheumatoid arthritis, multiple sclerosis, diabetes, atopic dermatitis and
asthma, as well as obesity and metabolic syndrome, all of which could
have their pathogenic origins in untoward reactivity of the immune
system to the microbiota. Whether dysbiosis is a cause or effect of these
disorders remains to be determined, but understanding the factors that
lead to alterations in the composition of the microbiota in these conditions promises to be informative, irrespective of their basis.
In this Review, we highlight advances in our understanding of the
immune mechanisms by which the dynamic interplay of the intestinal
microbiota and its host normally favours a homeostatic, mutualistic
relationship, as a basis for understanding the causes of breakdowns in
this relationship that lead to disease.

Co-evolution of the microbiota and adaptive immunity
Vertebrate evolution coincided with the emergence of the adaptive
immune system, the main components of which are T and B lymphocytes. The acquisition of genetic recombinatorial mechanisms for
generating diverse, anticipatory antigen-recognition receptors on T cells
and B cells allowed specific responses to a vast diversity of antigens,
and long-lived immune memory. Although evolutionary pressures that
have shaped immune strategies are often viewed in the context of host
defence, it has been proposed that the emergence of adaptive immunity

1

Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA; 2Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
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and the compartmentalization of the gut-associated lymphoid tissues (GALT) from the peripheral immune system were essential adaptations that allowed vertebrates to harness a complex intestinal microbiota. LTi cells develop in the fetal liver from a common lymphoid precursor that gives rise to all lymphoid cells. which seems to be far less complex than the microbiota of vertebrates3. exposure to new microbes. The development of ILFs is also dependent on LTi cells. and the recruitment and partitioning of B and T cells into B-cell follicles and T-cell zones that characterize secondary lymphoid tissues9. the intestinal microbiota is not only seeded by maternal bacterial species.INSIGHT REVIEW could have been driven as a means to foster. early vertebrates with adaptive immune mechanisms could begin to promote colonization of their alimentary tracts by exerting selective pressures that favoured resident microbes that were relatively innocuous. because infants born by Caesarean section — who are initially colonized by bacterial species of epidermal. Preparation for the adaptive immune response to neonatal colonization requires the prenatal actions of a subset of innate lymphoid cells (ILCs). Although environmental factors such as diet. Now extending to all jawed vertebrate taxa. perhaps so the neonate’s defences are not overwhelmed before they are fully developed. Similarly. In this view. The ‘pioneer’ species received from the mother seem to be important. by the maternal microbiota. xenobiotics. diverse intestinal microbiota. and adaptations that effect its efficient transport across the mucosal epithelium. each of these lymphoid tissues requires signals derived from the sensing of intestinal microbiota for their complete development. Peyer’s patches and MLNs develop prenatally. However. bacteriophages and intestinal infections have important roles in shaping the composition of the microbiota during this maturational window. irrespective of the composition of the mature microbiota. a substantial survival advantage would have been afforded to organisms that could harness the extended and more flexible metabolic capacity derived from a permanent. but its composition may also be reinforced and shaped by the maternal sIgA repertoire that is influenced. and remember. recruitment of a mature complement of immune cells. first contact could be deterministic. and their gastrointestinal tracts are similarly colonized soon after birth4. as long as the attendant infectious risk could be mitigated. During this initial period. placental mammals give birth to live young that are carried to term in utero and are nursed with milk that is rich in maternal antibodies. LTi cells are instrumental in prenatal organization of the development of lymphoid tissues. so the passive transfer of maternal sIgA has a considerable protective role against potential pathogens that could perturb the ecological trajectory of the infant’s intestinal microbiota. as well as promote. Microbiome effects on developing host-barrier defence Maturation of the intestinal mucosa and its GALT — Peyer’s patches of the distal ileum. breast milk provides abundant sIgA. in addition to the direct effect of maternal sIgA on the microbiota of the infant. although Caesarean-section-born infants lag behind those born transvaginally in their acquisition of the two bacterial divisions dominant in the adult microbiota (Firmicutes and Bacteroidetes). LTi cells disseminate to the MLN and Peyer’s patches anlagen. or both. the highest density of bacteria found in either organisms or the environment is in the human colon1. stimulating the development of these structures. they do catch up. In so far as microbial antigens that are bound by sIgA are handled by the innate immune system in a ‘tolerogenic’ mode. except cartilaginous fish and reptiles. but ILFs develop postnatally9. establishing a consortium that resembles that of adults8.10. Normally. In doing so. Support for this hypothesis comes from the study of the diversity of the microbiota in invertebrates. non-lymphoid structures of the intestinal mucosa that contribute to the establishment of host–microbiota mutualism are driven by colonization of the neonate. 1). Maternal sIgA also shields the neonatal immune system from its own microbiota. and the microbiota that colonize the gut. Thus. Maturation of the infant mucosal immune system takes months. isolated lymphoid follicles (ILFs) and mesenteric lymph nodes (MLNs) — is initiated by. The development of a broad repertoire of immune cells that could suppress. rather than vaginal. innate inflammatory mechanisms contingent on the threat level of the microbe they recognized would become invaluable. extended postnatally. This is 2 3 2 | NAT U R E | VO L 4 8 9 | 1 3 S E P T E M B E R 2 0 1 2 despite the fact that. but is initiated . Thus. In addition to a unique mix of nutrients and antimicrobial proteins that influence the ecology of the neonatal microbiota. rather than limit. both beneficial and detrimental members of the intestinal microbiota to foster maintenance of beneficial species at the expense of detrimental ones. termed lymphoid tissue inducer (LTi) cells (Fig. The intestinal microbiota of vertebrate species as divergent as rodents and zebrafish share similar complexity to that of humans. in turn. Conversely. The maternal–neonate metagenomic bond is. intestinal colonization. it also has immunomodulatory effects on the developing infant’s immune repertoire so as to indirectly influence its microbiota. partly owing to IgA’s poor fixation of complement. and contingent on. in breastfed infants delivered transvaginally. pioneer bacterial species might have substantial and lasting effects on the immune response. mother-to-child transmission in neonates delivered transvaginally rapidly shifts to skin and oral ecologies postpartum. it is anticipated that the merger of comparative studies in metagenomics and immunology will yield insight into the adaptive mechanisms that have allowed vertebrates to become an evolutionary success. including the components of the GALT. which has implications for the developing immune system of the infant. the neonatal immune system rapidly matures under the influence of the microbiota. Further. These antibodies provide passive transfer of immunity from mother to infant. origin — are predisposed to development of allergies and asthma later in life7. transfer of maternal sIgA to the infant seems to favour the establishment of regulatory immune networks in the infant that promote a mutualistic relationship with the microbiota. microbial colonization3. Adaptive immunity might have allowed this. the part the neonatal immune system plays is less clear. the emerging adaptive immune system would have had to acquire mechanisms for tempering innate immune responses programmed only for the clearance of microbes. Although data on comparative metagenomics are limited. It is tempting to speculate that the development of multimeric mucosal IgA. Maternal effects on the neonatal microbiome The greatest initial contribution to the composite human–microbiota ‘superorganism’ is the vertical transmission of components of the mother’s microbiota to the child at birth. Thus. The emergence of adaptive immunity provided a means to recognize. By adding new layers — such as secretory IgA (sIgA) — to existing innate barrier defences. That is. which is less diverse than that of the lower intestinal tract6. It may yet prove that we owe it to the bugs that have become ‘us. The survival benefits that accrued as a result of derivation of nutrients from a broader range of foods could have been a major factor in the evolutionary success of vertebrates3. What is clear is the initial and ongoing influence of breastfeeding on the infant’s microbiome. therefore. Although more work is needed to establish a comparative map of the microbiota in the digestive tracts of more vertebrate and non-vertebrate species. Unlike other vertebrates. The neonatal microbiota varies erratically until about 1-year-old when it stabilizes. The mucosal immune memory of the mother is thereby transmitted to her offspring. During fetal development. a homologue of sIgA was recently identified in bony fish5. intestinal colonization of neonates is dominated by transmission of bacteria from the maternal vaginal flora. such that these infants are later exposed to similar species as those delivered through Caesarean section.’ The microbiota and the developing immune system The mammalian immune system is perhaps the most elaborate example of the complex symbiotic relationship that has resulted from the co-evolution of vertebrates and their microbiota. providing one mechanism by which microbial ecologies tend to cluster in family members. the specificities of which have been shaped by the maternal microbiota. this unique class of immunoglobulin is adapted for interactions with the commensal microbiota and mucosal pathogens. but metabolically useful.

ILFs develop in the intestinal mucosa in intimate association with the overlying intestinal epithelium (Fig. from which they are endocytosed by dendritic cells in the subepithelial dome. the innate and adaptive immune systems constantly monitor the microbiota and are ‘informed’ of the dominant bacterial species that reside in proximity to the epithelium. initiating multiple events that affect the development or functional maturation of the mucosa and gut-associated lymphoid tissues. Unlike MLNs and Peyer’s patches. a. which is the receptor for the abundant product of Gram-negative bacteria. such as antimicrobial peptides16. where they release dimeric IgA for transport into the intestinal lumen. bacteria colonize the neonatal intestine immediately. This increase in TLR4 expression and signalling followed by down-regulation seems to represent a mechanism whereby the fetal epithelium is primed to transmit transient inflammatory signals on sensing the microbiota to promote an early immune response. for which class-switch recombination to produce IgA is T-cell dependent. but then becomes rapidly desensitized as an adaptation to the mounting bacterial load. IgA class-switching in ILFs can occur through T-cell-dependent and -independent pathways13. and in which Gram-negative bacteria are over-represented12. Similar to Peyer’s patches. This sensing also arms the intestinal epithelial cells for release of antimicrobial peptides. Shown from left to right: microbe-associated molecular patterns (MAMPs) sensed by pattern-recognition receptors on intestinal epithelial cells and dendritic cells adjacent to cryptopatches stimulate the further recruitment of B cells and T cells. which transport intact microbes or their products across the epithelial barrier. the response of IECs to lipopolysaccharide is markedly attenuated through the down-regulation of TLR4 and components of its signalling apparatus. T cells and B cells in preparation for the immune response to the microbiota. and cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Microbes also cross the epithelium and enter Peyer’s patches through M cells. whereas ILFs are found in non-mammalian vertebrates. stimulating ILF development to generate a lymphoid structure that is capable of supporting the maturation of B cells that produce sIgA. An additional immune mechanism that prepares the neonate for commensal colonization is the seeding of the intestinal epithelium with specialized intraepithelial lymphocytes before birth. ILFs develop from cryptopatches only after colonization by the intestinal microbiota. increased density of Paneth cells. Antigen-loaded dendritic cells in the Peyer’s patch interact with local lymphocytes to induce T-cell differentiation and T-cell-dependent B-cell maturation in the germinal centre to induce the development of IgAproducing plasma cells that home to the lamina propria. Within hours of exposure to the microbiota. Shown on the far right. but responds rapidly to perinatal colonization to accommodate the microbiota. Throughout life. suggesting that they are the evolutionary forerunners of the secondary lymphoid tissues of the GALT14 and may have evolved to accommodate. In this way. forming cryptopatches11. are significantly increased antecedent to intestinal colonization at birth15. Expression of — and signalling by — TLR4. causing the cryptopatches to develop into mature isolated lymphoid follicles. sensing of MAMPs stimulates the proliferation of intestinal epithelial cells in crypts. This. resulting in their increased depth and. 1). The importance of ILFs in regulating the microbiota is evident in mice that are devoid of these structures. which then migrate through the afferent lymphatics vessels (not shown) to a draining mesenteric lymph node to induce differentiation of effector T cells that traffic to the lamina propria. Recognition of peptidoglycan by NOD1 in IECs elicits production of CCL20 and β-defensin 3 that direct the recruitment of B cells to LTi–dendritic-cell clusters in cryptopatches to induce the expression of sIgA (ref. stimulates the recruitment of dendritic cells. as well as pathogens. cells. Intraepithelial lymphocytes seed the epithelium before birth.REVIEW INSIGHT a Prenatal b Postnatal Dendritic cell Bacteria Lumen Intraepithelial lymphocyte Dendritic cell MAMPs Goblet cell M cell Epithelium Lamina propria Antimicrobial peptides Dimeric IgA IgA+ cell T cell B cell Peyer’s patch Cryptopatch Paneth cell LTi cell Mesenteric lymph node Mature isolated lymphoid follicle Peyer’s patch Figure 1 | The gut-associated lymphoid tissue establishes perinatal hostmicrobiota mutualism in the intestine. in the small intestine. Intraepithelial lymphocytes intercalate between IECs where they exist in an activated state and can respond rapidly to microbial encroachment. an increasingly complex intestinal microbiota before specialized secondary lymphoid tissues emerged. lipopolysaccharide. MLNs and Peyer’s patches are unique to mammals. Central to sensing the colonizers of the intestinal tract is the expression of a diverse range of germline-encoded pattern-recognition receptors (PRRs) by intestinal epithelial cells (IECs) and immune cells resident in the gut. Both structures are strategically deployed to sample the microbiota through specialized microfold. intestinal intraepithelial lymphocytes help to maintain the integrity of the epithelial-cell barrier. or M.12). Postnatally. Dendritic-cell-mediated luminal sampling of microbial products or transcytosis of bacteria across the epithelium results in antigen loading of lamina propria dendritic cells. At least one of the microbial products that induces this process is peptidoglycan derived from Gram-negative bacteria. and promote. Prenatally. 1 3 S E P T E M B E R 2 0 1 2 | VO L 4 8 9 | NAT U R E | 2 3 3 . MAMPs are recognized — through mechanisms that are not well understood — by cells in the neonatal gut. The isolated lymphoid follicles release IgA-producing plasma cells — which are formed through T-cell-dependent and independent interactions — into the lamina propria. In addition. b. in turn. limit bacterial translocation and facilitate epithelium repair after injury by secreting soluble mediators. secondary lymphoid tissues (Peyer’s patches and mesenteric lymph nodes) and cryptopatches develop by the spatiotemporal recruitment of lymphoid tissue inducer (LTi) cells to sites of the developing intestine and supporting neurovascular structures. which cells of the intestinal mucosa use to detect microbe-associated molecular patterns (MAMPs) that are expressed by constituents of the resident microbiota. Like the GALT. the epithelium of the fetal and newborns’ intestine is incompletely adapted to dense bacterial colonization. These receptors include transmembrane Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) that reside on the cell surface or in endosomes. after birth when these cells cluster in the lamina propria below the intestinal crypts.

Indeed. proprionate and butyrate) that are the main nutrient source for colonic IECs.. are dependent on the terminal blood-group glycans 2 3 4 | NAT U R E | VO L 4 8 9 | 1 3 S E P T E M B E R 2 0 1 2 for colonization of the intestinal mucus and are less abundant in non-secretor genotypes. that contribute to epithelial restitution and repair. Muc2. Highly specialized barrier defences have evolved to confine the microbiota and resist pathogens. thereby promoting their retention in the collective (Box 1). such as trefoil factor. Reciprocity between the epithelium and the microbiota The epithelium is central to the orchestration of intestinal defences. In addition. and produce other metabolites (such as. proteolytic cleavage of Muc2’s polypeptide backbone in the outer layer results in its expanded volume and accessibility to colonization by components of the microbiota22. Innate pathways to sense and restrain the microbiota The intestinal tract is the largest barrier tissue in the human body (it has a surface area of about 300 m3 in adults). The importance of the mucus layer is evident in mice deficient for principal intestinal mucin. and a lamina propria populated by innate and adaptive immune cells that actively participate in homeostatic responses to restrain the microbiota without undue inflammation. frequencies or diversity of immune-cell populations at mucosal sites. The tight junctions that seal the interfaces of adjacent IECs segregate the epithelium into an apical. acetate and lactate) that are toxic to some pathogens23. The strategy is one of a layered defence that integrates a stratified mucous layer. As a mucosal tissue. receive a ‘secondary education’ from the microbiota to establish a durable immune repertoire that is crucial to the prevention of inflammatory diseases in childhood and adulthood. In particular. as well as those with Crohn’s disease99. The thickness and continuity of intestinal mucus differs regionally: it is thinner and discontinuous in the proximal small intestine and becomes thicker and continuous in the distal small and large intestine22. the assembly of type A. Bifidobacterium spp. These bacteria ferment complex O-linked mucin glycans to produce shortchain fatty acids (SCFAs) derived from mucin catabolism (for example. the intestinal epithelium continuously produces and is invested by a layer of mucus that is a first line of defence against microbes (Fig. and is both responsive to the microbiota and conditioned by it (Fig. showing some correlation with the local bacterial load (103–105 organisms per gram of luminal contents in the duodenum and jejunum.INSIGHT REVIEW Although the host has evolved elaborate developmental strategies to prepare for postnatal colonization. Butyrate produced by benign constituents of the microbiota also promotes increased release of mucin. The SCFAs also signal through BOX 1 Modulation of the microbiota by blood-group antigens An important aspect of the microbiota’s use of the intestinal mucous layer as an ecological niche is its decoration by blood-group antigens. M cells and enteroendocrine cells — develop from a common stem cell located near the base of the intestinal crypts. Maintaining the polarized structure of the epithelial barrier is crucial to its function. the dialogue between the host and microbiota. lumen-exposed surface and a basolateral surface anchored to the basement membrane. a postnatal time window is thought to exist in which regulatory T (Treg) cells17 and invariant-natural killer T (iNK T) cells18 that have received their ‘primary education’ in the thymus. which are a beneficial component of the microbiota. The mucus is stratified into two functionally distinct layers: a compact. cytokines and chemokines) to either promote immune quiescence at homeostasis or activate inflammatory immune responses when the epithelial barrier has been breached. The presence or absence of a functional FUT2 allele correlates strongly with the composition of the microbiota97. mucin glycans are nutrients for some constituents of the microbiota. This protein is encoded by FUT2. Given the predisposition to dysbiosis and its deleterious health effects in non-secretors. and conduit for. cells of the epithelium initiate responses that either promote the release of protective factors that are directed luminally (for example. germ-free or ‘germ-reduced’ mice have reduced size and cellularity of secondary lymphoid tissues as well as altered numbers. it is likely that evolutionary pressure to retain the defective FUT2 allele in the population is a result of mucin-linked blood-group glycans also serving as sites of attachment for mucosal viruses (such as noroviruses) so that those with a non-secretor genotype are protected100. . such as Bifidobacterium and Bacteroides spp. Analogous to blood-group antigens on erythrocytes. providing a positive-feedback loop for maintenance of the mucous barrier and its colonization by butyrate-producing commensals. and 1010–1012 organisms per gram in the colon). the intestinal epithelium is an active sensor of. Each cell type has a specialized. compared with conventionally raised mice. or internally (for example. Production of intestinal mucus is regulated by products of the microbiota. Components of the healthy microbiota therefore directly contribute to the barrier function of the intestine through their induction of mucin production and secretion by goblet cells. firmly adherent inner layer that is sparsely populated by bacteria and a more loosely structured. integral role in intestinal homeostasis. 2). should the barrier be breached. which is functional in most individuals (secretor genotype). Mucus is produced by goblet cells and is composed of heavily glycosylated mucin proteins. referred to as non-secretors) owing to a missense mutation. it seems that the protective benefits of colonization by Bifidobacterium spp. about 108 organisms per gram in the ileum. while maintaining its main function of nutrient uptake. The five main cell types that comprise the epithelium — absorptive enterocytes. Addition of the MAMP lipopolysaccharide or peptidoglycan stimulates the release of mucin by goblet cells and the rapid reconstitution of the colonic inner mucous layer19. the outer mucous layer provides an anchor for the attachment of bacteria of the microbiota that can establish biofilms that exclude pathogens. and spontaneously develop colitis21. secreted mucins and antimicrobial peptides) to directly restrain the microbiota. and thus mount abnormal responses to infection and injury. in addition to dietary glycans. Furthermore. as well as other protective molecules. the microbiota reciprocates by inducing maturation of the host’s immune system. Therefore. Not simply a passive barrier to microbial translocation. Paneth cells. non-adherent outer layer that is at least tenfold more densely populated by the microbiota22. Although both mucous layers have a similar Muc2-dominated composition. Therefore. These mice have increased translocation of commensal and pathogenic bacteria20. making it the most extensive portal for entry of commensal or pathogenic microbes. The non-secretor phenotype is associated with necrotizing enterocolitis and Gram-negative sepsis in premature infants98. goblet cells. In germ-free mice the mucous layer in the colon is highly attenuated. yet are poised for the induction of antimicrobial clearance responses and tissue repair. despite normal numbers of mucin-laden goblet cells. are a mutually beneficial evolutionary adaptation of this commensal to its host. 1).. B or Lewis-b glycans on intestinal mucins is contingent on the generation of the core H-glycan by the actions of FUT2. but is non-functional in a significant minority (about 20% of Caucasians. a relatively impenetrable but highly responsive epithelium. Depending on whether the membrane-associated PRRs are arrayed on the apical or basolateral surface of the IECs and on which side of the epithelial barrier MAMPs are detected.

to Large intestine Small intestine downregulate host inflammatory responses24.products that are secreted apically to restrict contact with the microbiota bial peptides. and a less densely cross-linked outer mucous layer. In addition. such as Reg-IIIγ. which contain high levels of bile salts and acid that have Although the intestinal mucous layer largely insulates the intestinal epithelium from direct interactions with the microbiota. microbiota to control the release of antimicrobial peptides by Paneth The strategic distribution of TLRs and NLRs on and within IECs cells.produces factors. which stimulates AMP production and promotes poorest coverage of protective mucous. at homeostasis. colonization of the outer mucous layer by commensals is an important adaptation that Outer mucous supports a stable host–microbiota relationship. ing MAMPs into the IEC cytosol where they are recognized by NLRs. This Inner characteristic is a result of the layer’s compact mucous Mucin layer physicochemical structure and its function as a reservoir for microbicidal products of the Apical epithelium. bacterial strains of the indigenous microbiota are non-invasive through PRR-dependent mechanisms. whether their recognition promotes pro-inflammatory sition and density in the small intestine that heighten susceptibility to responses or represses them. including α-defensins. in which a thicker colonization or penetration due to its high concentration of bactericidal AMPs. Several mechaCrohn’s disease28. inflammasome in colonic IECs have an altered microbiota that conAlthough this feature favours digestion and absorption of nutrients it fers increased susceptibility to colitis because of damage to the colonic also seems to make the epithelium in this region particularly vulner. NOD2.and rial load22. mucins and antimicrobial peptides). large intestine. proximal small intestine22. which is retained in the IL-22 mucous layer after being shuttled across the Paneth Goblet Enterocyte Colonocyte Tight cell cell junction epithelium by polymeric immunoglobulin plgR receptor (pIgR) (Fig. α-defensins are synthesized and stored in Paneth-cell epithelium. bacterial antimicrobial effects. the release vation of PRRs typically promotes pro-inflammatory innate responses. as well as specialized Paneth cells in the bases of small intestinal crypts continually sense the for Gram-negative bacteria also contribute to microbiota to induce the production of antimicrobial peptides (AMPs).nized. sIgA Lumen layer In contrast with the outer mucous layer. synthesis of which requires signals from basolaterally. that is organized into a dense. as well as commensalinner mucous layer excludes most bacteria specific secretory IgA (sIgA). The increased susceptibility to colitis that results from able to entry by the microbiota and pathogens. which was the first susceptibility gene linked to transmitted to mucosal immune cells limit inflammation. Colonic IECs also regulate the composition of microbiota however. the inner LTi cell NK-22 sIgA-producing mucous layer is a ‘killing field’ that few pathoplasma cell gens or commensals have evolved strategies Lamina propria to penetrate.epithelial cells (IECs) are integrated into a continuous. However. to the inner mucous layer where it is released by proteolytic cleavage of pIgR. are thought to result in altered microbiota compo. These IECs are arrayed with a range of PRRs and gene expression in IECs through PRRs31. which are small. the epithelium also microbicides unique to Paneth cells. which is ferried across IECs from their basolateral surface. These factors signal immune cells residing internal of the the microbiota26. the bacterial NLRP6 deficiency is transmissible to wild-type mice.suggests this cytokine has an important role. How deficiency of the NLRP6 over a million-fold fewer bacteria per unit of luminal contents than the inflammasome results in an altered microbiota is incompletely defined. including microbes. Enterocytes. that are secreted bial peptides. the bases of the crypts of the small intestine are home to metabolites and components are able to permeate this zone and alter many Paneth cells. Because Reg-IIIγ is selec. in the small intestine. 25). including antimicrobial peptides Basolateral that are specialized to kill different classes of microbes and sIgA. and colonocytes in the large it is likely that antimicrobial peptides specific intestine. from the lumen. 2). single cell layer that is divided into apical and tively bactericidal for Gram-positive bacteria. innate lymphoid cells. by the antibacterial lectin Figure 2 | The barrier function of the intestinal epithelium.by the polymeric immunoglobulin receptor (pIgR). and the secretion of so the intestinal epithelium had to evolve strategies to mitigate these active α-defensins has been shown to control the composition of the responses for commensals such that. basolateral regions by tight junctions.epithelium30. particularly in the intestinal lamina propria (Fig. particularly in the terminal ileum where the factors to allow them to attach to or invade IECs thereby introduchighest density of Paneth cells are found. in part. Mice deficient in the NLRP6 and therefore less potent activators of NLRs. A similar spatial segadherent inner mucous layer. Responding to the microbiota. 3). The inner mucous layer is largely impervious to bacterial been identified in the colon. Distinct subpopulations of intestinal Reg-IIIγ (ref. The region of the intestinal tract with the AhR-expressing LTi and NK-22 cells. the epithelial barrier integrity. rial. Pathogenic bacteria possess virulence intestinal inflammation. owing to the more vigorous peristaltic although reduced interleukin (IL)-18 levels in NLRP6-deficient mice motility of the proximal small intestine. more highly cross-linked inner proteoglycan gel that forms an IECthe microbe-sparse zone. with dysbiotic flora is a contributory factor. Deficiencies of antimicrobial peptide production. which rapidly clears mate. where it is bound even in the face of a substantially higher bacte. in part. In contrast with other antimicro. such as chemokines and cytokines. such as occur has a considerable effect on whether bacterial MAMPs will be recogin NOD2 mutants. also has the greatest exposed epithelial surface area owing to its prominent villous structure. The outer layer is highly regation of bacteria from the epithelium has colonized by constituents of the microbiota. highly cationic (for example. Goblet cells produce mucin. The lumen of the proximal small intestine is also the entry point for the contents of the gall bladder Reciprocity between the epithelium and innate immune cells and stomach. Effectively. This is.29. 1 3 S E P T E M B E R 2 0 1 2 | VO L 4 8 9 | NAT U R E | 2 3 5 . produce IL-22. Actigranules without the need for sensing of MAMPs. Thus. This microbe-sparse zone is enforced. of Paneth-cell granules is induced by MAMPs. and if so. including RORγt. cytokine signals microbiota27. indicating that a loads in this region are the lowest along the length of the intestine. encodes an NLR that is important in sensing the nisms by which this anti-inflammatory state is favoured have emerged. However. In addition to the epithelial are specialized for the production and release of abundant antimicro.REVIEW INSIGHT G-protein-coupled receptors on IECs. In the intact epithelium. the AMPs inner mucous layer provides a relatively impermeable barrier against the microbiota.

which initiates inflammatory responses by innate and adaptive immune cells with the aim of eradicating the invading bacterium. Also like IECs. thereby terminating its transactivation of pro-inflammatory 2 3 6 | NAT U R E | VO L 4 8 9 | 1 3 S E P T E M B E R 2 0 1 2 Figure 3 | The epithelial-innate-adaptive continuum in response to microbial antigens. in turn. should contact occur. and promotes development and maintenance of Treg cells and IgA+ plasma cells. which is central to induction of pro-inflammatory gene expression downstream of all PRRs. including the secretion of TGFβ and IL-10 by iTreg cells and the secretion of IL-10 by macrophages. Although phagocytosis of commensal bacteria induces pro-IL-1β in intestinal macrophages. viruses and injury Mucins and AMPs sIgA IEC BAFF and APRIL IgA+ plasma cell TSLP IL-33 IL-25 TGFβ TGFβ IL-6 IL-1 IL-18 TGFβ IL-10 TGFβ. proliferation TGFβ. This is despite their retention of highly active phagocytic and bactericidal activities39. induce the development of induced Treg (iTreg) cells through a TGFβ. IL-33 and IL-25. MAMPs stimulate the secretion of cytokines (including TSLP. the latter of which can transition to the former as a result of IL-23 or IL-12 signalling. By contrast. thereby blocking nuclear transport of NF-κB (ref. PGE2). which are activated by MAMPs . Detection of flagellin on the ‘host’ side of the intestinal epithelial barrier results in epithelial-cell activation. Thus. Contact of IECs with these commensals inhibits IκB degradation. IL-1 and IL-18) and intestinal dendritic cells and macrophages (including IL-6. Antigens presented by CD103+ dendritic-cells favour the development of Treg cells and IgA+ plasma cells that ‘home’ to the lamina propria at which they repress inflammatory responses to the microbiota37. IECs secrete thymic stromal lymphopoietin (TSLP). including NK-like cells. including products of tryptophan metabolism and prostaglandins (for example. In the face of pathogen invasion. Dendritic cells. which helps to protect the epithelial barrier. respond to pro-inflammatory cytokines to upregulate IL-22. MAMPs stimulate the secretion of pro-inflammatory cytokines by IECs (including. and IL-17A and IL-17F. the anti-inflammatory balance of the intestine is maintained by inhibiting or dampening potential effector responses. Like IECs. Treg cell-derived TGFβ and epithelial-derived BAFF and APRIL promote development of IgA+ plasma cells to ensure an abundant supply of sIgA in the lumen that further limits microbial interaction with the epithelium. LTi cells. but reflects the limited entry of commensal bacteria or their products into the cytosol in which they can activate NLRs — despite their uptake and degradation in phagolysosomes. impaired signalling or both. Release of NF-κB for nuclear localization is contingent on the phosphorylation of IκB. IL-6. In response to the microbiota.INSIGHT REVIEW a Eubiosis b Dysbiosis Commensal bacteria Pathogenic bacteria. At homeostasis. IL-6 TH17 Dendritic cell IL-23 IL-10 IL-12 TH1 Macrophage NK cells Epithelial barrier maintence IL-22 LTi cell IFNγ IL-22 Epithelial proliferation IL-17A Neutrophil IL-17F recruitment γδIEL MAMPs derived from commensals are largely restricted to interactions with apically accessible TLRs. which is expressed on the basolateral aspects of the epithelium where it can detect the repeated flagellin monomers that make up bacterial flagellae32. peroxisome-proliferation-activated receptor-γ (PPAR-γ). IL-1. which suppresses NF-κB-dependent pro-inflammatory signalling in intestinal macrophages and dendritic cells. in addition to host mechanisms that normally restrain direct contact between commensals and IECs. Bacteroides and Lactobacillus spp. can further dampen NF-κB signalling by enhancing the nuclear export of NF-κB by inducing increased expression of the nuclear receptor family member. whether through decreased expression. by which it is targeted for ubiquitylation and protesomal degradation downstream of PRR signalling. intestinal macrophages normally express lower levels of TLRs and are hyporesponsive to TLR signalling to dampen inflammatory responses to the commensal microbiota. Active NF-κB dimers are sequestered in the cytosol by association with IκB complexes. IECs also produce abundant TGF-β. a. TLR-activated IECs can directly promote T-independent development of sIgA producing plasma cells in ILFs by the release of both B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL)38. b. but some commensals have also evolved strategies that actively dampen TLR signalling in IECs. differentiation. the receptor for flagellin.or NLRC4-containing inflammasomes. IL-25. which seem to be functionally dampened by tonic exposure to the microbiota. Intestinal innate lymphoid cells. IL-33. IL-23 and IL-12) that induce development of the effector CD4+ T cells TH1 and TH17. eubiotic conditions. co-adaptation of the microbiota and host have provided mechanisms that suppress proinflammatory engagement of PRRs in the intact epithelium. and γδIELs. The importance of flagellin as an immune-activating MAMP and an antigen targeted by adaptive immune cells is reflected in its high representation among antigens bound by serum antibodies from colitic mice and in patients with Crohn’s disease33. mucosal injury or dysbiosis. PPAR-γ binds NF-κB in the nucleus and shuttles it back to the cytoplasm. inhibit activation of the classical NF-κB pathway. its cleavage by caspase-1 to produce the active form requires NLRP3. Through multiple mechanisms. 34).and retinoic acid (RA)dependent process. RA iTreg Immune cell activation. expression of TLRs on the basolateral aspects of IECs can signal a barrier breach by both commensals and pathogens. IECs express other factors that limit pro-inflammatory responses of mucosal immune cells. which promote tolerogenic activities of a subset of intestinal dendritic-cells defined by expression of integrin αEβ7 complex (also known as CD103)36. genes35. Apical expression of TLRs and restricted access to cytosolic NLRs are adaptations to constrain interactions with luminal microbes. Bacteroides spp. In addition to cytokines. this inflammatory anergy is probably multifactorial. The epithelium also supports tolerance of the microbiota by conditioning intestinal dendritic-cells through directional release of immunomodulatory cytokines into the lamina propria. IECs secrete mucins and AMPs that limit microbial interaction with epithelial cells. and TGFβ) by IECs that promote development of tolerogenic macrophages and dendritic cells. In addition. which are involved in neutrophil recruitment. Under homeostatic. This is exemplified by TLR5.

Adaptive immunity in homeostatic responses to microbiota The interplay between the microbiota. fragilis with the colonic mucosa.REVIEW INSIGHT that are more effectively delivered into the cytosol by pathogenic.63.42.50. Myeloid cells of the innate immune system are the main targets for regulatory actions of IL-10 (ref. When the adaptive immune response is recruited. IL-17 or both in response to microbiota-induced production of IL-23 by macrophages and dendritic cells. However. are relatively resistant to inflammation driven by their microbiota.48. which is required for these cells’ development and function9. in a continuous feedback loop with the microbiota. and production of the cytokines IL-22. they are only one subset of a growing family of ILCs that have emerged as important contributors to intestinal homeostasis and barrier defence in the postnatal immune system41. ILCs are distributed in the intestinal lamina propria and GALT. IL-17A and IL-17F target innate immune cells. 58.(T regulatory cells 1 (Tr1)) are each characterized by their production of IL-10. This transcription factor is involved in TH1 cell development. which lack B and T cells. at steady state. The capsular polysaccharide-A moiety of the common commensal Bacteroides fragilis mediates interaction of B. Regulatory CD4+ T cells include subsets that are distinguished on the basis of their expression of the transcription factor. Importantly. Therefore. RAG-deficient mice.57. in turn. with which they share many functional features. Foxp3+ (Treg) or Foxp3. including the intestine. This compartmentalization of mucosal immunity is a result of the programming of adaptive immune cells to travel back to the mucosae following their differentiation in Peyer’s patches or MLNs. IL-10-deficient mice develop spontaneous. Foxp3. The nonredundant role of IL-10 in intestinal immune homeostasis is wellestablished. The diversity of ILC subsets seems to parallel that of CD4+ T cells. The frequencies of these T cells are considerably elevated in the intestine relative to other tissues52. as are a subset of natural-killer-like cells (referred to as NK-22 or ILC22 cells). Remarkably. However. ILC production of lymphotoxin provides an important amplifying loop for the production of IL-22 by ILCs. and to CD4+ T cells of the TH17 lineage (discussed later) is their expression of the transcription factor retinoic acid-related orphan receptor (ROR)γt. reflecting the outgrowth of two pathogenic bacterial strains: Klebsiella pneumoniae and Proteus mirabilis. transfer of the microbiota from TRUC mice to immunocompetent mice transfers disease. Regulatory T-cell responses to the microbiota CD4+ Treg cells are essential for maintenance of mutualism with the microbiota. RAG-deficient mice develop spontaneous intestinal inflammation resembling ulcerative colitis (known as T-bet−/− RAG−/− ulcerative colitis (TRUC) mice)51. phagocytes in the intestinal lamina propria are conditioned to mount inflammatory responses against pathogens that deliver MAMPs to cytosolic sensors. Thus. which suppress the development of pro-inflammatory innate and effector T-cell responses to avert excessive inflammation. respectively. 59). LTi cells are particularly important to barrier defence against bacterial incursions43. Akin to its essential role in GALT development. 45). Remarkably. despite the absence of an adaptive immune system. indicating that Foxp3. Although deficiency of IL-10 that is limited to Foxp3+ Treg cells also induces colitis. 61). IL-17A and IL-17F (ref. Polysaccharide-A promotes expansion of colonic IL-10-expressing Foxp3+ Treg cells. AhR signalling is required both for ILC maintenance and IL-22 production48. the antigen-specific-receptorlacking ILCs are recruited to mucosal immune responses mainly by cytokines. it is typically limited to the mucosal tissues such that systemic immunity is not generated. This is largely owing to compensatory increases in ILCs. whether derived from the same or distinct members of the microbiota. increases IL-22 production by ILCs49. In addition to RORγt and AhR. polymorphisms in the IL-10 locus confer susceptibility to IBD in humans64. in which they are poised to respond rapidly to microbes that penetrate the epithelial defences. to enhance antimicrobial defence and epithelial barrier integrity. much of our understanding of the inflammatory potential of the commensal microbiota has been garnered through models in which regulatory pathways have been disrupted54. IL-10-producing T cells can be induced to develop in response to specific commensals or their products. stimulating dendritic cell production of IL-23 that. they are crucial in the early host response to enteropathogenic bacteria41. driven by reactivity to antigens of the microbiota. although IL-10 signalling in CD4+ T cells also seems to be contributory62. but to efficiently clear commensals in a non-inflammatory manner. its severity is reduced. 60). Finally. Although non-T-cells produce IL-10. Indeed. Disease is a result of overexpression of TNFα by dendritic cells and an absence of Treg cells. through the TLR2–MyD88 pathway66. The 1 3 S E P T E M B E R 2 0 1 2 | VO L 4 8 9 | NAT U R E | 2 3 7 . another transcription factor shared between innate and adaptive immune cells that influences the composition of the microbiota is T-bet. RORγt+ ILCs also express the aryl hydrocarbon receptor (AhR) with which they sense microbiota metabolites and xenobiotics45.CD4+ T cells contribute to the protective IL-10 response. the dysbiosis in TRUC mice highlights the importance of innate immune cells in regulating the composition of the microbiota and is evidence that a dysbiotic flora can drive disease in otherwise healthy hosts. Although ILCs can contribute to intestinal pathology under certain circumstances46. bacteria40. rather than commensal. The crucial role of Treg cells in immune homeostasis to the microbiota is well-documented by the consequences of these cell’s absence54. results in unopposed effector T-cell responses and IBD. Common to these cells.47. Treg-cell deficiency. Although details of the mechanisms responsible for T-bet-dependent restraint of the microbiota remain to be defined. RORγt+ ILCs seem to be the main source of IL-22 at steady state and. when deficient for T-bet. which seem to share many features with LTi cells44. which are produced by IECs or intestinal myeloid cells (dendritic cells and macrophages). IL-10 deficiency that is restricted to total CD4+ T cells results in spontaneous colitis that has a severity comparable with that in mice with global loss of IL-10 (ref. one of the main immunoregulatory cytokines required for immune tolerance of the intestinal microbiota. G-CSF and CXCL8) that induce increased neutrophil production and recruitment. The essential role of TLR in sensing the microbiota in this process is evident by the absence of disease in germ-free IL-10-deficient mice and mice deficient for both IL-10 and MyD88 (ref. Innate lymphoid-cells response to epithelial barrier breach Although LTi cells are indispensable in the development of the GALT. antigen presentation by intestinal dendritic cells favours the development of regulatory CD4+ T cells. and earlyonset IBD has been linked to mutations in IL-10 receptor components that impair signalling65. unremitting colonic inflammation driven by IL-23 and the TH17 pathway56. T-cell-derived IL-10 is crucial for intestinal immune homeostasis. control these competing T-cell fates55. Under pathogen-free conditions. Furthermore. a portion of the sIgA response that contributes to partitioning of commensal organisms away from the epithelium is generated in ILFs without the requirement for T cells13. irrespective of the means by which it is induced. facilitating both colonization and activation of an anti-inflammatory cascade66. IL-22 is a member of the IL-10 cytokine family that acts on epithelial cells of barrier tissues. and is also expressed by a distinct subset of ILCs. These cytokines stimulate epithelial -cell secretion of antimicrobial peptides that inhibit or kill bacteria in the vicinity of the epithelial cell surface. and microbiota-induced Treg cells affect the composition of the microbiota53. Remarkably. release IL-22. intestinal epithelium and innate and adaptive immune cells at homeostasis favours the dominance of regulatory networks that prevent inflammation or immune-mediated disease. the innate defences are sufficiently robust that much of the host response to the microbiota progresses without involvement of CD4+ T-cell-dependent responses. stromal cells and epithelial cells to induce cytokines and chemokines (for example. The largely non-overlapping TCR specificities of regulatory and effector T-cell subsets in the colonic lamina propria and associated lymphoid tissues suggest that distinct antigenic epitopes.

which are more restricted in their tissue distribution. TH17 cells have developmental ties with Treg cells through their mutual requirement for the abundant intestinal cytokine TGFβ (ref. as well as a similar effector cytokine repertoire. microbial antigens that are identified as products of a pathogen are likely to be remembered as such through their imprinting of an effector T-cell response. This bacterium populates the ileum and caecum and has long been known to be a potent activator of intestinal immune responses77. T cells that express IFNγ or both IL-17 and IFNγ. In mice. Specifically. exert similar effects in humans. Furthermore. 70) with intestinal ILCs. an unusually potent. Of note. Induction of TH17 cells by SFB provides protection against gut pathogens78. TH17 cells in particular. there are no studies using otherwise complete microbiota that are devoid of B. Whether at steady state. in the context of an inflammatory response. although there seems to be a proclivity of certain components of the microbiota to promote Treg-cell development. in countries where these infections are less common the main effector T-cell subsets resident in the gut express cytokines characteristic of TH17 and TH1 cells. To date. seemingly owing to their superior ability to elicit TGFβ production in the intestinal mucosa68. However. fragilis or this specific collection of Clostridium spp. responding to infection or chronically inflamed as a result of IBD. TH17 cells retain a high capacity for divergent cytokine expression profiles and function. At homeostasis. or plasticity. including CD103+ dendritic cells and IECs in the intestine. which is required for TH17 differentiation and its deviation away from induced Treg programming. fragilis. In addition to IL-6. the TH17 developmental pathway is distinguished by considerable plasticity71. In a new twist on TGFβ’s role in this process. may. which are thought to be the most ancient of effector T-cell subsets4. the reverse is less apparent. 73). However.87 to override Treg-cell induction. Although Treg-cell dominance is the default at homeostasis. Thus. A cocktail of Clostridium species. the largest deployment of effector CD4+ T-cells in the healthy immune system is in the intestines. therefore. Finally. in addition to effectors that express IL-17. Candidatus arthromitus or segmented filamentous bacteria (SFB)72. 66). IL-1β (ref. drives the efficient expansion of Treg cells in the colons of germ-free mice. recent studies report their role in IgA class-switch recombination in the gut. naive CD4+ T-cell recognition of antigens derived from the microbiota favours induced Treg-cell development by virtue of the production. In a further example of the developmental plasticity of Treg cells. alcohol dehydrogenase and one of three retinal-specific aldehyde dehydrogenases. induced Treg cells were found to down-modulate Foxp3 and acquire features of follicular helper T cells . seem to be more resistant to reprogramming to become Foxp3+ regulatory cells.or anti-inflammatory cues. it is unclear whether SFB. allowing divergent functional programs contingent on local pro. the shared dependence of induced Treg and TH17-cell development on TGFβ provides an elegant means to alternately divert programming of naive CD4+ T cells from a homeostatic. the adaptive immune system has evolved to direct the development of distinct CD4+ T-cell fates by different APC subsets and the microbe-induced factors they produce. TH17 cells share developmental requirements for RORγt and AhR (ref. 4). fragilis is absent from the microbiota of 20–30% of humans. IL-23 (ref. In contrast with induction of Treg cells by B. microbial antigens that promote induced Treg responses at homeostasis. suggesting that general amplification of TH17 effector cells can be host-protective. B. representing another arm of Treg cell function in promoting immune homeostasis to the microbiota. 3). 74) and even ATP derived from commensal bacteria75. Although the intestines mount robust TH2 responses to helminth infestations.. retinoic acid is either repressed85 or co-opted by pro-inflammatory pathways86. In common with TH17 cells. this does not seem to be a unique property of any one microbial component. established effector T cells. Accordingly. microbe-clearing response contingent on the cofactors integrated with TGFβ signalling4 (Fig. IL-17F and IL-22. including TGFβ. The contribution of the microbiota to intestinal TH17-cell development is highlighted by the virtual absence of this subset in germ-free mice72. or related organisms. of the vitamin A metabolite all-trans-retinoic acid82–84. Balancing regulatory and effector responses To balance accommodation of the microbiota and the need to mount host defences against microbial invasion. minor constituents of the microbiota can amplify intestinal TH17 cell numbers. sensing of a single constituent of the intestinal microbiota can promote 2 3 8 | NAT U R E | VO L 4 8 9 | 1 3 S E P T E M B E R 2 0 1 2 autoimmunity in extraintestinal tissues. microbe-tolerant response to an inflammatory. seem to have evolved to bolster mucosal barrier defences to promote mutualism with the microbiota. but not unique. by intestinal dendritic cells. 88). and is largely driven by the microbiota. Under conditions in which microbial antigens promote production of pro-inflammatory cytokines by dendritic cells. Notably. The potency of retinoic acid as a cofactor for TGFβ-dependent development of induced Treg cells — and suppression of TH17 development — and its constitutive production by a regulatory subset of intestinal dendritic cells at steady state reflect the robust default pathway to T-cell-mediated regulation. but devoid of B. whether they are derived from the TH17 pathway or not. including TH17 cells. fragilis69. reflecting substantial redundancy in the system to ensure that Treg-cell dominance is established. effector CD4+ T-cells are perpetually engaged in the host–microbiota dialogue by favouring regulatory benefits at homeostasis or pathological consequences when dysregulated. Effector T-cell responses to the microbiota Similar to Treg cells and B cells. Clostridium-dependent Treg expansion occurs independently of MyD88 through mechanisms yet to be defined68. Although a last line of defence. The relative contributions of TH1 cells to immune protection or pathogenesis remain to be elucidated. reprogram induced Treg cells to generate an effector T-cell response that breaks the ‘tolerance’ to that microbe. Remarkably. When acted on by pro-inflammatory cytokines.INSIGHT REVIEW expression of TLR2 on CD4 T-cells suggests there is the capacity for direct regulation by microbial products that favours polysaccharideA-dependent Treg-cell responses over TH1 responses67.81. and perhaps reflecting an aspect of shared TGFβ-dependent programming that favours multipotency. default induction or expansion of Treg cells can be achieved by colonization of germ-free mice with a defined altered Schaedler flora (ASF) that consists of eight species of the microbiota dominated by Bacteroides distasonis. because monoassociation of mice with SFB induces TH17-mediated inflammatory arthritis79 and multiple-sclerosis-like symptoms in the experimental autoimmune encephalomyelitis (EAE) model80. induced Treg cells can down-regulate Foxp3 and up-regulate RORγt (ref. Retinoic acid is derived from vitamin A by the sequential actions of the ubiquitous enzyme. although there are other known TLR2 ligands that do not promote induction of Foxp3 or IL-10 (ref. TH17 induction by SFB is not entirely benign. mostly comprised of clusters IV and XIVa. induced Treg cells display developmental plasticity that influences adaptive immunity to the microbiota. and Treg cells can be converted into IL-17or IFNγ-expressing effectors during infection89. 3). By contrast. and has suggested that many of the TH1 cells found in the intestine arise from the TH17 pathway (Fig. indicating the existence of other pathways to Treg-cell development. Vitamin A is not synthesized by the host so its influence on the regulatory tone of the mucosal immune response is predicated from adequate dietary intake. although Foxp3+ Treg cells may be diverted to effector responses. TGFβ has long been recognized as the principal switch factor for development of IgA-producing B cells. the intestine contains. Accordingly. TH17 cells can give rise to IFNγ producers that resemble classical TH1 cells.76. multiple microbiota-dependent factors favour TH17 development in the intestines. including IL-17A. inducer of TH17 cells69 is the Clostridia sp. leaving open the issue of the level of redundancy in this process. after their commitment to the TH17 pathway. Similar to the ability of a limited quorum of commensal bacterial species to disproportionately influence induced Treg-cell development. At present. This has been demonstrated in humans and mice71.

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